Note: Descriptions are shown in the official language in which they were submitted.
CA 02781379 2012-11-09
TOPICAL FORMULATIONS FOR THE PREVENTION OF SEXUALLY TRANSMITTED
DISEASE AND METHODS OF PRODUCING THE SAME
FIELD OF THE INVENTION
[0002] This invention relates to topical protective
formulations for use in the prevention of the spread of sexually
transmitted diseases (STDs); and particularly to unique topical
formulations including a plurality of film forming excipients,
which act in concert to provide a barrier to help inhibit the
transmission of STDs.
BACKGROUND OF THE INVENTION
[0003] Sexually transmitted diseases (STDs) are a universal
concern, effecting millions of individuals and straining health
care systems. More than 20 different sexually transmitted
diseases have been identified by the medical community and
generally fall into two groups, including bacterial types (e.g.,
gonorrhea, chlamydia and syphilis) and viral types (human
immunodeficiency virus (HIV), human papilloma virus (HPV) and
hepatitis). The numerous diseases affect men, women and
children of all backgrounds, races and economic classifications.
Despite years of research and educational programs, the
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transmission of sexually transmitted diseases remains a global
health threat. Although specific methods of transmission may
vary depending on the disease-causing organism, STDs are usually
transmitted to the uninfected person through injured or exposed
skin or mucous membranes during sexual contact.
[0004] Treatments may be available for some types of STDs
(e.g. antibiotic treatment for gonorrhea or chlamydia).
However, most people who suffer from these types of STDs are
unaware that they have the disease and therefore do not get the
necessary treatment. Moreover, because of the sociological
impact and generally negative stigma associated with these
diseases, people are reluctant to seek such treatments. The
continued emphasis on educating the population as to the use of
"mechanical barriers" such as condoms has helped to decrease the
morbidity of most STDs but more preventative methods need to be
developed to prevent STD transmission.
[0005] Chemical actives such as microbicides, antimicrobials,
and spermicides, most notably, nonylphenoxypoly(ethyleneoxy)-
ethanol (also referred to as nonoxyno1-9) have been used in
topical formulations to effectively reduce the rate of STD
transmission, especially when used in conjunction with
prophylactics. However, many of these chemical actives are harsh
and have been shown to induce local irritation, inflammation,
and ulcerations, which might actually favor the transmission of
STDs. Thus, a need exists for topical formulations that do not
cause irritation and will help inhibit the spread of STDs,
especially when used in combination with condoms, and thereby
provide an additional degree of protection from contamination,
should the condom become damaged.
PRIOR ART
[0006] Although there are numerous patents and publications
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directed to formulations containing chemical actives, such as,
microbicides, antimicrobials, spermicides, and drug delivery
carriers (liposomes, micelles), none of the known prior art
teach formulations comprising non-irritating agents that provide
a physical barrier to the permeation of pathogens.
[0007] U.S. Patent Application 2003/0143189 Al to Askill et
al., is directed to a method of treating skin lesions by forming
a polymeric film over the lesions to inhibit proliferation of
infectious agents in the lesions. These compositions also
include one or more chemical agents in combination therewith.
[0008] U.S. Patent 6,835,717 to Hildreth discloses a method
of reducing the risk of a sexually transmitted pathogen by
contacting a pathogen within the composition which consists of
P-cyclodextrin.
[0009] U.S. Patent No. 6,821,958 to Hershline discloses a
method of preventing viral transmission using an alkylsulfate
derivative of sulfated dextrin as a topical formulation.
[0010] U.S. Patent 6,582,711 to Asmus et al., discloses an
antimicrobial hydroalcoholic composition having a cationic
polymeric thickener.
[0011] U.S. Patent No. 6,355,235 to Cone et al., consists of
an antibody capable of trapping sperm and a pharmaceutical
carrier.
[0012] U.S. Patent No. 6,328,991 to Myhling discloses a
chemical composition to prevent the transmission of sexually
transmitted diseases comprising nonylphenoxpoly-(ethyleneoxy)-
ethanol, benzalkonium chloride and povidone iodine.
[0013] U.S. Patent 5,439,685 to Augros is a composition of an
agent active against microorganisms responsible for sexually
transmitted diseases together with a film-forming agent such as
dimethylpolysiloxane, and benzalkonium chloride as a
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spermicidal.
[0014] U.S. Patent 4,952,411 to Fox, Jr. et al., is a
composition of silver sulfadiazine, alone or in combination with
chlorhexidine or sodium deoxycholate (antimicrobial and
detergent).
SUMMARY OF THE INVENTION
[0015] The purpose of this invention is to provide non-
irritating protective formulations to be used as an adjunct in
preventing the spread of a broad range of sexually transmitted
diseases. The products of the present invention can be formulated
as a topical lotion, cream, solution, emulsion, or the like, and
will be hereinafter referred to as creams. Applicant's previous
patent demonstrated that the use of antimicrobial/antiviral
active agents in conjunction with film-forming excipients in the
following formulations possessed unique skin protective barrier
properties with enhanced persistence that inhibit "skin to skin"
and "sore to sore" transmission of pathogens (e.g., viruses,
bacteria, fungi, parasites, ectoparasites and mycoplasmas)
linked to communicable diseases.
[0016] Applicants have now discovered that equivalent skin
protective barrier properties, with enhanced persistence, which
are also effective in providing the inhibition of "skin to skin"
and "sore to sore" transmission of pathogens (e.g., viruses,
bacteria, fungi, parasites, ectoparasites and mycoplasmas)
linked to communicable diseases, can be realized in the absence
of an antimicrobial/antiviral agent.
[0017] Skin protectant products are regulated under CFR 21
Part 347 "Skin Protectant Drug Products for Over the Counter
Human Use". The official description of a skin protectant is "a
drug product that temporarily protects injured or exposed skin
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or mucous membrane surfaces from harmful or annoying stimuli,
and may help provide relief to such surfaces." These
regulations cover applicable ingredients, as well as labeling
requirements for over the counter skin protectants. Active
ingredients officially classified as skin protectants
compositions as well as certain combinations of these
compositions are listed in the CFR 21 Sec. 347.10, reproduced in
Table 1 below. In accordance with the instant invention, the
phrase "a skin protectant composition provided in a skin
protecting effective concentration" will be understood to mean
any of the following ingredients within their designated range
of concentrations:
CA 02781379 2012-06-27
TABLE 1
[0018] These include any of the following within the
concentration range specified:
Ingredient Concentration
Allantoin 0.5 to 2.0 %
Aluminum hydroxide gel 0.15 to 5.0%
Calamine 1.0 to 25.0 %
Cocoa Sutter 50.0 to 100.0%
Cod liver oil 5.0 to 13.56 %(in accordance with Sec.
347.20(a)(1) or (a)(2), provided the product
is labeled so that the quantity used in a
24-hr period does not exceed 10,000 USP
Units vitamin A and 400 USP Units
cholecalciferol.
Colloidal oatmeal 0.007 minimum; 0.003 minimum in
combination
with mineral oil in accordance with Sec.
347.20(a)(4).
Dimethicone 1.0 to 30.0%
Glycerin 20.0 to 45.0%
Hard fat 50.0 to 100.0%
Kaolin 4.0 to 20.0%
Lanolin 12.5 to 50.0%
Mineral oil 50.0 to 100.0%; 30.0 to 35.0% in
combination
with colloidal oatmeal in accordance with
Sec. 347.2-0(a)(4).
Petrolatum 30.0 to 100.0%
Topical starch 10.0 to 98.0%
White petrolatum 30.0 to 100.0%
Zinc acetate 0.1 to 2.0%
Zinc carbonate 0.2 to 2.0%
Zinc oxide 1.0 to 25.0%
[0019] It has been discovered that incorporation of at least
one of the aforementioned skin protectants compositions listed
in Table 1 in combination with other film forming excipients, in
particular, film-forming emollients (e.g., Cetostearyl alcohol,
Cetyl alcohol), silicone-containing excipients/skin protectants
(e.g., polydimethylsiloxane derivatives of varying viscosities,
utilized either singly or in combination, and marketed under
names such as Dimethicone 20 and Dimethicone 12500), emulsifying
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=
agents (e.g. selected from Cetearyl alcohol (a mixture of fatty
alcohols, predominantly stearyl and cetyl alcohols,
polyoxyethylene ethers of a mixture of high molecular mass
saturated fatty acids (mainly cetyl alcohol and stearyl alcohol,
having a number of ethylene oxide residues in the
polyoxyethylene chain, e.g. 20, 12 or the like, and referred to
as Ceteareth-20, Ceteareth-12, or the like, and/or mixtures
thereof), humectants (e.g. glycerin and anhydrous lanolin) and
chelating compounds(e.g. disodium edetate) in a formulation for
topical application results in a product that temporarily
protects injured or exposed skin or mucous membrane surfaces
from harmful or annoying stimuli, thereby preventing cross-
contamination of pathogenic microorganisms responsible for
sexually transmitted diseases (e.g., Herpes simplex virus type 1
and type 2 (HSV-1, HSV-2), human immunodeficiency virus (HIV),
or the like) through skin or mucous membrane surfaces. The novel
formulation products of this invention are persistent in that
they form a film or barrier on healthy or even damaged skin.
[0020] The hydrophobic portions of the instant formulations
utilize a combination of film-forming excipients, including skin
protectant(s) listed in Table 1, silicones and silicone
derivatives or like equivalents, and film-forming emollients.
The emulsifiers throughout the continuous aqueous phase disperse
these ingredients. They liquefy and spread over the skin as a
result of exposure to body heat. This forms a physical
hydrophobic layer, which resides on the skin surface (including
mucosal membranes) and provides a barrier, which would inhibit
penetration of liquids, and pathogens that are primarily
hydrophilic in nature. When used in combination with consistent
and careful use of condoms, the products of the present
invention help inhibit the spread of STDs and protect the skin
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from contamination should the condom become damaged.
[0021] Accordingly, it is an objective of the instant
invention to teach various topical protective formulations to be
used in preventing the spread of a broad range of sexually
transmitted diseases.
[0022] Another objective of the present invention is to teach
formulations which are condom compatible, meaning that they are
latex friendly and provide effective lubricity.
[0023] It is yet another objective of the instant invention
to teach skin protective formulations wherein contact with the
skin results in the formation of a hydrophobic skin protective
surface layer.
[0024] It is yet another objective of the instant invention
to teach skin protective formulations wherein contact with the
skin results in the formation of a mechanical barrier skin
protective surface layer.
[0025] Yet another objective of the invention is to teach
products formulated as a lotion, cream, solution, emulsion, or
other topically applied product.
[0026] Other objects and advantages of this invention will
become apparent from the following description, wherein are set
forth, by way of illustration and example, certain embodiments
of this invention.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Detailed embodiments of the instant invention are
disclosed herein, however, it is to be understood that the
disclosed embodiments are merely exemplary of the invention,
which may be embodied in various forms. Therefore, specific
functional and structural details disclosed herein are not to be
interpreted as limiting, but merely as a basis for the claims
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and as a representation basis for teaching one skilled in the
art to variously employ the present invention in virtually any
appropriately detailed structure.
[0028] Zinc oxide is an inert, non-toxic chemical compound
with the chemical formula of ZnO. Zinc Oxide can be used as a
skin barrier. When applied to skin, Zinc Oxide acts as a
mechanical barrier that physically excludes isolates and
prevents the skin from any contact with harmful stimuli. Zinc
Oxide is often used in creams or lotions and provides a
continuous barrier, which also helps prevent the loss of active
ingredients due to friction and rubbing. Because of its inert,
non-toxic characteristics and general non-solubility in water,
it can be applied to skin as many times as may be needed. While
zinc oxide is the preferred skin protectant composition of the
present invention, other suitable skin protectant compositions
and their amounts effective to provide skin protection as listed
in Table 1 above could be used herein (e.g., Dimethicone).
[0029] Glycerin (INCI name: Glycerin) is a non-irritating
humectant and film former. It is also water-soluble. Moreover,
glycerin is compatible with latex products and provides extended
lubricity, which makes it a common base for many products
designed for genital use.
[0030] Lanolin is a humectant isolated from wool-bearing
animals such as sheep. It is a product of the sebaceous gland
and consists mostly of a mixture of cholesterol and the esters
of several fatty acids. It has many commercial uses, including
within the medical and cosmetic industries.
[0031] Benzalkonium Chloride is a member of the quaternary
ammonium compounds. These compounds are a group of ammonium
salts in which organic radicals have been substituted for all
four hydrogens of the original ammonium cation. Benzalkonium
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Chloride has been reported to be an effective anti-viral wetting
agent in the prevention of transmission of viral diseases such
as HIV and herpes simplex virus. Benzalkonium Chloride is also
listed in the FDA Topical Antimicrobial Drug Products Monograph
as a First Aid Antiseptic.
[0032] The phrase "film-forming emollient" refers to any
excipient suitable for cosmetic and pharmaceutical applications,
which forms a water-repelling film. According to a preferred,
albeit non-limiting embodiment, the film-forming emollients are
cetyl alcohol and cetostearyl alcohol. Cetyl alcohol (IUPAC
name of 1-hexadecanol) is a member of the alcohol class of
compounds. It is a solid organic compound and belongs to a
group of fatty alcohols. In addition to its use as an
emollient, it is often used in the cosmetic industry as a
surfactant in shampoos, emulsifiers or thickening agents in the
manufacture of skin creams and lotions. Cetostearyl alcohol is
a blend of cetyl alcohol and stearyl alcohol, two fatty alcohols
derived from vegetable sources.
[0033] The phrase "silicone-containing excipient" refers to
any silicone or silicone derivatives, including silicone-based
skin protectants, suitable for cosmetic and pharmaceutical
applications, which acts as an emollient and forms a water-
repelling film, including silicone oils. In addition to skin
barriers, silicone and silicone oils are highly substantive on
the skin. As a result of this property, silicon and silicone
oils are often used in topical formulations, such as creams and
lotions, to improve the substantivity of active ingredients on
the skin.
[0034] After applying the topical formulations to the skin
and removing volatile substances, the film formed as a result of
using a silicone-containing excipient helps to maintain the
CA 02781379 2012-06-27
active ingredient in close contact with the skin and prevents
the loss of the active ingredient by abrasion. The ability to
form hydrophobic films, which can easily be applied, and spread
over skin accounts for high resistance to wash-off and rub-off.
Use of silicones in topical formulations over petroleum-based
products is more desirable because silicones do not exhibit the
negative aesthetics of petroleum and, unlike petroleum, are
known to be compatible with the materials used to manufacture
condoms. According to one non-limiting embodiment, Dimethicone
(preferably Dimethicone 20 cSt and Dimethicone 12500 cSt) is
preferred. Dimethicone is a highly pure, non-volatile silicone
fluid, which is colorless and odorless. It can be used as a
lubricant and emollient skin protectant.
[0035] Ceteareth-12 is part of a family with the INCI name of
Ceteareth-n and refers to polyoxyethylene ethers of a mixture of
high molecular mass saturated fatty alcohols. The "n" indicates
the average number of ethylene oxide residues in the
polyoxyethylene chain. Ceteareth-12 is a non-toxic surfactant,
which is frequently used as an emulsifier in the cosmetic
industry. The mixture of Cetearyl alcohol and Ceteareth-20
(EMULGADE 1000NI, Cognis Corporation) is a non-ionic, self-
emulsifying base commonly used in the production of oil/water
creams and lotions.
[0036] Disodium Edetate, having the chemical name of disodium
(ethylene-dinitrilo) tetra-acetate dihydrate, is also commonly
known as the disodium salt of EDTA. The chemical acts as a
chelating compound by preventing ingredients from binding to
trace elements that may be present.
[0037] Excipients useful in forming the skin protective
creams, according to the present invention are described in the
following non-limiting example.
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EXAMPLE 1
[0038] In formulating a batch of a skin protective cream
according to the invention, active ingredients and excipients
useful in the manufacture of this product, a particularly
effective product resulted when ingredients were utilized within
the following approximate ranges:
ACTIVE INGREDIENTS/EXCIPIENT WT/WT % RANGES
Water phase
(1) DEIONIZED WATER Q.S.
(2) EDETATE DISODIUM 0.01-0.1
(3) ZINC OXIDE 1.0-8.0
(4) GLYCERIN (USP) 2.0-10.0
Oil Phase
(5) DIMETHICONE 20 10.0-20.0
(6) DIMETHICONE 12500 3.0-10.0
(7) CETEARYL ALCOHOL and/or CETEARETH-20 6.0-10.0
(8) CETEARETH-12 0.5-3.0
(9) ANYHDROUS LANOLIN 0.5-3.0
(10) CETOSTEARYL ALCHOHOL 1.0-5.0
(11) CETYL ALCOHOL 1.0-5.0
[0039] A preferred, albeit non-limiting procedure for
manufacture of the formulation comprises the steps of:
Procedure:
1. Heat to 75 C -Dimethicone 20, Dimethicone 12500, CetcY)ryl
Alcohol and Ceteareth-20 (available as EMULGADE 1000 NI from Cognis),
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Ceteareth-12 (available as (EUMULGIN B1 from Cognis), Anhydrous Lanolin,
Cetostearyl alcohol and Cetyl alcohol. Allow the materials to
melt.
2. Dissolve Disodium Edetate in the deionized water (USP).
3. Heat Step #2 to 75-78 C.
4. Disperse the Zinc Oxide in the Glycerin to form a homogeneous
dispersion.
5. With high speed mixing, slowly add the materials from Step #3
(Water phase) to the materials from Step #1 (Oil phase). Initiate
cooling.
6. When at 60 C; add the dispersion from Step#4 to the
materials from Step #5 (Emulsion).
7. When at 50 C, reduce mixing speed.
9. When at 40 C, further reduce the mixing speed.
10. When at 25 C stop mixing.
[0040] While not wishing to be bound to any particular
theory, it is believed that these film forming excipients and
active ingredient form a neutral and hydrophobic layer barrier
which is also believed to interact with the skin thereby having
a stabilizing effect upon the hydrophobic layer, which results
in the enhanced persistence of the product. The use of a
silicone-containing skin protectant, e.g. Dimethicone 20 and
Dimethicone 12500, or a like equivalent, acts in coordination
with at least one of the skin protectants compositions as
defined in CFR 21 Sec. 347.10, e.g. Zinc Oxide, or others from
Table 1, excipients and the film-forming emollients, and melts
when contacted with the heat of the body. This in turn forms a
physical hydrophobic layer that provides a barrier, which
appears to inhibit penetration of liquids, and sexually
transmitted pathogens (viral, bacterial) which are primarily
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hydrophilic in nature. This property helps protect the user
from contamination due to sexual contact with infected
individuals.
[0041] In order to ascertain any differences between the use
of the formulation as described herein, and a formulation
additionally containing an antiviral, e.g. benzalkonium
chloride, the following experiment was carried out.
SKIN BARRIER FORMULATION
% (w/w)
Dimethicone 20 (Dow coming Q7-9120 Silicone Fluid 15.030060120
Dimethicone 12500 (Dow Corning Q7-9120 Silicone
5.010020040
Fluid 12500 I cSt).
Zinc Oxide, USP 2.004008016
Cetearyl Alcohol & Ceteareth-20 (Emulgade 1000 NI,
8.016032064
Cognis)
Glycerin, USP 5.010020040
Ceteareth-12 (Eumulgin Bl, Cognis) 1.002004008
Edetate Disodium, USP 0.050100200
Anhydrous Lanolin, USP 1.002004008
Cetostearyl Alcohol, NF 3.006012024
Cetyl Alcohol, NF 2.004008016
Purified Water USP 57.865731460
100.00
TABLE 1
[0042] In accordance with the teachings of the present
invention, the skin barrier formulation illustrated in Table 1
was prepared. Additionally, a second formulation was prepared,
to which the antiviral ingredient Benzalkonium Chloride
(Benzalkonium Chloride 50% Solution,NF) was added in an amount
of 0.20% w/w.
[0043] A test protocol was followed in order to evaluate the
barrier function of the cream product against fluid and virus
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transmission alone and with the addition of Benzalkonium
Chloride. The challenge virus selected was Herpes Simplex Virus
Type 2, ATCC VR-734.
[0044] Three pieces of filter paper were weighed and placed
onto a sterile glass Petri dish. Following, a piece of porous
membrane (pore size 10 pm) was placed on top of the filter paper
layer [except for Filter Paper Only (No Membrane) Control]. The
carrier was pre-incubated at 37 1 C (Actual, 37 C) for 10 1 minutes
(Actual, 10 minutes) with the lid off prior to further
manipulation.
[0045] To determine efficacy as a viral barrier, 1.00 g of
test agent was spread evenly across the upper side of the
membrane area. Thereafter, 0.2 mL of the challenge virus was
applied evenly to the treated membrane. The carrier was
covered, sealed in parafilm, and incubated at 37 1 C (Actual,
37 C) for 30 1 minutes (Actual, 30 minutes).
[0046] To determine efficacy as a moisture barrier, during
the carrier preparation/pre-incubation step, 1.00 g of test
agent was spread evenly across the upper side of the membrane
area. Following, the carrier was incubated at 37 1 C (Actual,
37 C) for 10 1 minutes (Actual, 10 minutes). Thereafter, 0.2 mL
of cell culture medium was applied evenly to the treated
membrane. The carrier was covered, sealed in parafilm, and
incubated at 37 1 C (Actual, 37 C) for 30 1 minutes (Actual, 30
minutes). It was assayed for moisture adsorption only.
[0047] To determine moisture penetration of the filter paper,
after the contact time, the membrane - if applicable, was
carefully lifted and removed. The filter paper layer was weighed
to measure moisture adsorption.
[0048] To determine viral penetration, the filter paper layer
was placed in a 50-mL sterile tube with 15-mL of recovery medium.
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The filter paper layer was squeezed with a cell scraper.
Following, the tube was vortexed on a vortex-type mixer for 1-2
minutes and held at room temperature for about 5 minutes. The tube
was then vortexed using a vortex-type mixer for an additional 1-2
minutes; it was then centrifuged at 5000 rpm for 5 minutes. The
supernatant was collected and passed through a 0.45 pm syringe
filter prior to use in diluting and plating.
Media and reagents:
RPMI 1640 + 5% Newborn Calf Serum + 0.5% Polysorbate 80
RPMI 1640 + 5% Newborn Calf Serum
Filter paper, ashless circles, 47 mm diameter, WhatmanTM
No. 41
10-pm membrane filters, circles, 47 mm diameter, type TCTP
[0049] The results are summarized in Table 2, wherein it is
seen that the efficacy of the comparative formulations with and
without Benzalkonium Chloride were equivalent in their ability to
block the penetration of both viral and moisture challenges.
Sample ID Cream Input Virus Virus Volume Normalized
Dosage Virus* Recovered* Reduction* of virus/ Moisture
(Logto (Loglo (Log-to media* gaina
TCID50) TC1050) TCI050) (mL) (g)
Skin Barrier
Formula of
0.2 mL
Table Number 1- - 1.00g 4.33 0.36 3.01 ** l.32 0.00
(virus)
Virus
Test Sample
Skin Barrier
Formula 1 plus
Benzalkonium 0.2 mL
- 1.00g 4.71 0.38 3.01 ** 1.70 0.02
Chloride - (virus)
Virus Test
Sample
TABLE 2
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, .
* Results represent the averaged data from three replicates.
** A complete blockade of virus was observed in all three
replicates.
a normalized based on the moisture gain from a Cream-only (no
virus or media) sample
[0050] The scope of the claims should not be limited by
particular embodiments set forth herein, but should be construed
in a manner consistent with the specification as a whole.
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, .
* Results represent the averaged data from three replicates.
** A complete blockade of virus was observed in all three
replicates.
a normalized based on the moisture gain from a Cream-only (no
virus or media) sample
[0050] The scope of the claims should not be limited by
particular embodiments set forth herein, but should be construed
in a manner consistent with the specification as a whole.
17
